title: Dual role of lipoxin A4 in pneumosepsis pathogenesis.
abstract: Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC-2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis.
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, SC, Brazil.
authors.forename: Regina
authors.initials: R
authors.lastname: Sordi
authors.forename: Octávio
authors.initials: O
authors.lastname: Menezes-de-Lima
authors.forename: Verônica
authors.initials: V
authors.lastname: Horewicz
authors.forename: Karin
authors.initials: K
authors.lastname: Scheschowitsch
authors.forename: Laís F
authors.initials: LF
authors.lastname: Santos
authors.forename: Jamil
authors.initials: J
authors.lastname: Assreuy
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology; D053583:Interleukin-1beta / Q000097:blood; D007710:Klebsiella Infections / Q000150:complications / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000276:immunology*; D044045:Lipoxins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000037:antagonists & inhibitors; D018805:Sepsis / Q000209:etiology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; D006538:Heptanoic Acids; D053583:Interleukin-1beta; D044045:Lipoxins; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; D014409:Tumor Necrosis Factor-alpha; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; C509690:tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide; C033373:butyloxycarbonyl-phenylalanyl-leucyl-phenylalanyl-leucyl-phenylalanine
keywords: 5(S),6(R),7-trihydroxyheptanoic acid methyl ester; 5(S),6(R)-Lipoxin A(4); AhR; BAL; BML-111; BOC-2; CLP; FPR2/ALX; LO; LXA(4); Lipoxin A(4); N-t-Boc-Phe-Leu-Phe-Leu-Phe; Sepsis; Trp-Arg-Trp-Trp-Trp-Trp-CONH(2); WRW(4); aryl hydrocarbon receptor; bronchoalveolar lavage; cecal ligation and puncture; formyl peptide receptor-2; lipoxygenases